We have identified a truncated SR-family protein that has potent antiviral activity against HIV-1, HIV-2, and SIV, but no activity against MLV. Ectopic expression of the truncated SR-protein in human or mouse cells restricts the nuclear entry of HIV pre-integration complexes. Selection of HIV resistant to this factor leads to mutation in the virus capsid protein. Notably, these HIV mutants lose the ability to infect nondividing cells, and one mutation in particular interferes with HIV infection of terminally differentiated macrophages. We believe this to be a significant advance. In the era of molecular HIV studies, the discrete elements within HIV that are required for the infection of nondividing cells has proven to be a vexing question despite the sustained interest of gene therapists and HIV researchers. We are currently seeking cellular proteins targeted by the antiviral factor to better understand the machinery HIV interacts with in the infection of nondividing cells. We are also studying how the capsid mutations alter the biology of early HIV replication. In related work, we have also discovered dominant restrictions in human cells that interfere with HIV after entry but can be overcome by mutation of the viral core. These studies may provide new drug targets for antiviral therapy. Identification of HIV host cell factors will also enable the improvement of cell culture and animal models to study HIV transmission and replication. [Corresponds to KewalRamani Project 1 in the April 2007 site visit report of the HIV Drug Resistance Program]